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Sometimes it is not the drug that scuppers a clinical trial. Prana Biotechnology announced today that it is halting the much anticipated phase II/III clinical trial of its Alzheimer drug PBT1—before it even starts (see statement on Prana website).

PBT-1, aka clioquinol or iodochlorhydroxyquin, showed promise in an early pilot study (see ARF related news story), but Prana is pulling the drug because of unacceptable levels of a toxic impurity in the formulation. The impurity, a di-iodo form of clioquinol, is a side-product of the synthesis process, and Prana states that “attempts to reduce the impurity to safe levels are not likely to be successful in a timely manner and that further development of PBT1 is not warranted.”

The news is not necessarily a nail in the coffin for metal-protein attenuating compounds like clioquinol (see related ARF Live Discussion on the theory behind the development of clioquinol). The company has one other such drug, PBT2, in the pipeline. PBT2 does not contain iodine, so it cannot be marred by exactly the same problems as its forerunner. PBT2 is currently undergoing phase I safety trials in Holland.—Tom Fagan.

Comments

Prana's decision to cancel the phase II/III "PLACQUE" clinical trial of PBT1 is, of course, disappointing. PBT1 (clioquinol or "CQ") is an old drug that required redevelopment of its synthetic route to meet today's GMP standards. As was highlighted in Prana's press release, during large-scale synthesis, unacceptably high levels of a mutagenic impurity were found. The levels of this di-iodo derivative in the batch made for the PLACQUE trial exceeded new international impurity guidelines, and therefore this batch could not be used in the clinical trial. The trial thus could not proceed.

So why not try to purify or resynthesize CQ? While it may be theoretically possible after additional work to satisfactorily reduce or even eliminate the levels of the di-iodo impurity (either by new synthetic chemistry or by new purification techniques), this investment in time and money may not be the best option for several reasons, the first being that Prana has a pipeline of new, custom-designed drug candidates which have already passed testing in the same preclinical models for Alzheimer disease where CQ showed efficacy: The most advanced of these, PBT2, has already entered phase I clinical trials. In addition, the remanufacturing of PBT1 would require considerable time, quite possibly putting its testing behind PBT2, anyway. Finally, as Prana explained, the di-iodo contaminant cannot form with PBT2 because its structure does not contain any iodine.

Speaking on behalf of our research teams working on the metallochemistry of Aβ, we want to point out that the trial cancellation is neither because of problems with the underlying science, nor because of new concerns about the efficacy of the drug or its class (Metal Protein Attenuating Compounds, MPACs). We believe that the underlying science remains strong and can be used to screen for and test new drug candidates. Clioquinol established the principles that are involved in targeting abnormal metal-Aβ interactions to identify new orally bioavailable MPACs as drug candidates for Alzheimer disease.

In summary, being mindful that Prana has PBT2 and other candidate compounds in its development pipeline, it would seem prudent to shift emphasis to the testing of PBT2 and the newer drug candidates.

We hope this clarification is helpful.

Disclosure: Dr Ashley Bush and Dr Rudolph Tanzi disclose that they are shareholders and paid consultants for Prana.

Robert Peers Solo practitioner and independent researcher; Founder, National Institute of Good Health

Posted: 24 Apr 2005

The real nail in the coffin for any drug whatsoever for the blind empirical treatment of Alzheimer's disease is knowing what causes the disease, which is (quite simply) vacuum steam-deodorized, Vitamin E -depleted polyunsaturated vegetable oils (soya bean oil being both the most deficient in the vitamin, and also the most widely consumed food oil). When governments come to realize, by a process of scientific persuasion, that the correction of low Vitamin E levels in refined food oils will completely prevent both Alzheimer's disease and its prenatal partner, Attention Deficiet Hyperactivity Disorder, the market for blind empirics will shrink rapidly, thus ending the Alzheimer Disease Industry. I predict a closing date of 2007.